Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Airborne polycyclic aromatic compounds contribute to the induction of the tumour-suppressing P53 pathway in wild double-crested cormorants.

Polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and PAH-like compounds are known or probable environmental carcinogens released into the environment as a by-product of incomplete combustion of fossil fuels and other organic materials. Studies have shown that exposure to PACs in the environment can induce both genotoxicity and epigenetic toxicity, but few studies have related PAC exposure to molecular changes in free ranging wildlife. Previous work has suggested that double-crested cormorants (Phalacrocorax auritus; DCCO) exhibited a higher incidence of genetic mutations when their breeding sites were located in heavily industrialized areas (e.g., Hamilton Harbour, Hamilton, ON, Canada) as compared to sites located in more pristine environments, such as in Lake Erie. The aim of this study was to determine if airborne PACs from Hamilton Harbour alter the tumour-suppressing P53 pathway and/or global DNA methylation in DCCOs. Airborne PACs were measured using passive air samplers in the Hamilton Harbour area and low-resolution mass spectrometry analysis detected PACs in livers of DCCOs living in Hamilton Harbour. Further hepatic and lung transcriptional analysis demonstrated that the expression of the genes involved in the DNA repair and cellular apoptosis pathway were up-regulated in both tissues of DCCOs exposed to PACs, while genes involved in p53 regulation were down-regulated. However, global methylation levels did not differ between reference- and PAC-exposed DCCOs. Altogether, data suggest that PACs activate the P53 pathway in free-ranging DCCOs living nearby PAC-contaminated areas.

A phylogenetic test of sympatric speciation in the Hydrobatinae (Aves: Procellariiformes).

Phylogenetic relationships among species can provide insight into how new species arise. For example, careful consideration of both the phylogenetic and geographic distributions of species in a group can reveal the geographic models of speciation within the group. One such model, sympatric speciation, may be more common than previously thought. The Hydrobatinae (Aves: Procellariformes) is a diverse subfamily of Northern Hemisphere storm-petrels for which the taxonomy is unclear. Previous studies showed that Hydrobates (formally Oceanodroma) castro breeding in the Azores during the cool season is sister species to H. monteiroi, a hot season breeder at the same locations, which suggests sympatric speciation by allochrony. To test whether other species within the subfamily arose via sympatric speciation by allochrony, we sequenced the cytochrome b gene and five nuclear introns to estimate a phylogenetic tree using multispecies coalescent methods, and to test whether species breeding in the same geographic area are monophyletic. We found that speciation within the Hydrobatinae appears to have followed several geographic modes of divergence. Sympatric seasonal species in Japan likely did not arise through sympatric speciation, but allochrony may have played a role in the divergence of H. matsudairae, a cool season breeder, and H. monorhis, a hot season breeder. No other potential cases of sympatric speciation were discovered within the subfamily. Despite breeding in the same geographic area, hydrobatine storm-petrels breeding in Baja California (H. microsoma and H. melania) are each sister to a species breeding off the coast of Peru (H. tethys and H. markhami, respectively). In fact, antitropical sister species appear to have diverged at multiple times, suggesting allochronic divergence might be common. In addition, allopatry has likely played a role in divergence of H. furcata, a north Pacific breeder, and H. pelagius, a north Atlantic breeder. This study demonstrates that a variety of mechanisms of divergence have played a role in generating the diversity of the Hydrobatinae and supports the current taxonomy of the subfamily.

COS-Speech: protocol to develop a core outcome set for dysarthria after stroke for use in clinical practice and research.

BACKGROUND: Dysarthria after stroke is when speech intelligibility is impaired, and this occurs in half of all stroke survivors. Dysarthria often leads to social isolation, poor psychological well-being and can prevent return to work and social lives. Currently, a variety of outcome measures are used in clinical research and practice when monitoring recovery for people who have dysarthria. When research studies use different measures, it is impossible to compare results from trials and delays our understanding of effective clinical treatments. The aim of this study is to develop a core outcome set (COS) to agree what aspects of speech recovery should be measured for dysarthria after stroke (COS-Speech) in research and clinical practice. METHODS: The COS-Speech study will include five steps: (1) development of a long list of possible outcome domains of speech that should be measured to guide the survey; (2) recruitment to the COS-Speech study of three key stakeholder groups in the UK and Australia: stroke survivors, communication researchers and speech and language therapists/pathologists; (3) two rounds of the Delphi survey process; (4) a consensus meeting to agree the speech outcomes to be measured and a follow-up consensus meeting to match existing instruments/measures (from parallel systematic review) to the agreed COS-Speech; (5) dissemination of COS-Speech. DISCUSSION: There is currently no COS for dysarthria after stroke for research trials or clinical practice. The findings from this research study will be a minimum COS, for use in all dysarthria research studies and clinical practice looking at post-stroke recovery of speech. These findings will be widely disseminated using professional and patient networks, research and clinical forums as well as using a variety of academic papers, videos, accessible writing such as blogs and links on social media. TRIAL REGISTRATION: COS-Speech is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database, October 2021 https://www.comet-initiative.org/Studies/Details/1959 . In addition, "A systematic review of the psychometric properties and clinical utility of instruments measuring dysarthria after stroke" will inform the consensus meeting to match measures to COS-Speech. The protocol for the systematic reviews registered with the International Prospective Register of Systematic Reviews. PROSPERO registration number: CRD42022302998 .

Exploring dimensions of quality-of-life in survivors of stroke with communication disabilities - a brief report.

BACKGROUND: People with communication disabilities post-stroke have poor quality-of-life. OBJECTIVES: We aimed to explore the association of self-reported communication disabilities with different dimensions of quality-of-life between 90 and 180 days post-stroke. METHODS: Cross-sectional survey data were obtained between 90 and 180 days post-stroke from registrants in the Australian Stroke Clinical Registry recruited from three hospitals in Queensland. The usual follow-up survey included the EQ5D-3L. Responses to the Hospital Anxiety and Depression Scale, and extra questions (e.g. communication disabilities) were also collected. We used χ2 statistics to determine differences. RESULTS: Overall, 244/647 survivors completed the survey. Respondents with communication disabilities (n = 72) more often reported moderate to extreme problems in all EQ5D-3L dimensions, than those without communication disabilities (n = 172): anxiety or depression (74% vs 40%, p < .001), pain or discomfort (58% vs 39%, p = .006), self-care (46% vs 18%, p < .001), usual activities (77% vs 49%, p < .001), and mobility (68% vs 35%, p < .001). Respondents with communication disabilities reported less fatigue (66% vs 89%, p < .001), poorer cognitive skills (thinking) (16% vs 1%, p < .001) and lower social participation (31% vs 6%, p < .001) than those without communication disabilities. CONCLUSIONS: Survivors of stroke with communication disabilities are more negatively impacted across different dimensions of quality-of-life (as reported between 90 and 180 days post-stroke) compared to those without communication disabilities. This highlights the need for timely and on-going comprehensive multidisciplinary person-centered support.

Structural and functional spatial dynamics of microbial communities in aerated and non-aerated horizontal flow treatment wetlands.

A multiphasic study using structural and functional analyses was employed to investigate the spatial dynamics of the microbial community within five horizontal subsurface flow treatment wetlands (TWs) of differing designs in Germany. The TWs differed in terms of the depth of media saturation, presence of plants (Phragmites australis), and aeration. In addition to influent and effluent water samples, internal samples were taken at different locations (12.5 %, 25 %, 50 %, and 75 % of the fractional distance along the flow path) within each system. 16S rRNA sequencing was used for the investigation of microbial community structure and was compared to microbial community function and enumeration data. The microbial community structure in the unaerated systems was similar, but different from the aerated TW profiles. Spatial positioning along the flow path explained the majority of microbial community dynamics/differences within this study. This was mainly attributed to the availability of nutrients closer to the inlet which also regulated the fixed biofilm/biomass densities. As the amount of fixed biofilm decreased from the inlet to the TW outlets, structural diversity increased, suggesting different microbial communities were present to handle the more easily utilized/degraded pollutants near the inlet vs. the more difficult to degrade and recalcitrant pollutants closer to the outlets. This study also confirmed that effluent water samples do not accurately describe the microbial communities responsible for water treatment inside a TW, highlighting the importance of using internal samples for investigating microbial communities in TWs. The results of this study reinforce an existing knowledge gap regarding the potential for TW design modifications which incorporate microbial community spatial dynamics (heterogeneity). It is suggested that utilizing step-feeding could allow for improved water treatment within the same areal footprint, and modifications enhancing co-metabolic processes could assist in improving the treatment of more difficult to degrade or recalcitrant compounds such as micropollutants.

Sub-lethal effects of calcium dinonylnaphthalenesulfonate on Western clawed frog embryos.

Naphthalene sulfonic acids (NSAs) are used as additives in lubricants, dyes, and greases and commonly act as surfactants in many industrial processes. The calcium salt of dinonyl NSA (calcium dinonylnaphthalenesulfonate; CaDNS) is listed among thousands of chemicals identified as priorities for assessment by the Government of Canada's Chemical Management Plan due to the limited toxicity data. The purpose of this study was two-fold: 1) to establish the toxicity of CaDNS to Western clawed frog (Silurana tropicalis) embryos and 2) to assess the sub-lethal effects and mechanisms of toxicity of CaDNS in amphibians through targeted gene expression and metabolite analyses. Frog embryos were exposed to water overlying sand spiked with a range of concentrations of CaDNS (17-1393 µg/g) over a 72-h period. Results indicated significantly higher mortality and presence of malformations in frog larvae exposed to over 672 µg/g CaDNS in the sand (14 ng/mL CaDNS in the water) compared to control treatments. An overall decrease in the glutathione redox cycle was observed, including decreases in relative mRNA levels of enzymes (glutathione S-transferase (gst), glutathione reductase (gsr), glutathione peroxidase (gpx)) and decreases in the glutathione (GSH) and glutathione disulfide (GSSG) metabolite concentrations. In addition, transcript levels of genes involved in antioxidant capacity and essential amino acid metabolites decreased significantly in embryos exposed to low levels of CaDNS. This is the first study to assess the toxicity of NSAs in amphibians, contributing important data to aid in the assessment of NSAs.

Polycyclic aromatic compounds (PACs) in the Canadian environment: The challenges of ecological risk assessments.

Ecological risk assessments (ERAs) of polycyclic aromatic compounds (PACs), as single congeners or in mixtures, present technical challenges that raise concerns about their accuracy and validity for Canadian environments. Of more than 100,000 possible PAC structures, the toxicity of fewer than 1% have been tested as individual compounds, limiting the assessment of complex mixtures. Because of the diversity in modes of PAC action, the additivity of mixtures cannot be assumed, and mixture compositions change rapidly with weathering. In vertebrates, PACs are rapidly oxygenated by cytochrome P450 enzymes, often to metabolites that are more toxic than the parent compound. The ability to predict the ecological fate, distribution and effects of PACs is limited by toxicity data derived from tests of a few responses with a limited array of test species, under optimal laboratory conditions. Although several models are available to predict PAC toxicity and rank species sensitivity, they were developed with data biased by test methods, and the reported toxicities of many PACs exceed their solubility limits. As a result, Canadian Environmental Quality Guidelines for a few individual PACs provide little support for ERAs of complex mixtures in emissions and at contaminated sites. These issues are illustrated by reviews of three case studies of PAC-contaminated sites relevant to Canadian ecosystems. Interactions among ecosystem characteristics, the behaviour, fate and distribution of PACs, and non-chemical stresses on PAC-exposed species prevented clear associations between cause and effect. The uncertainties of ERAs can only be reduced by estimating the toxicity of a wider array of PACs to species typical of Canada's diverse geography and environmental conditions. Improvements are needed to models that predict toxicity, and more field studies of contaminated sites in Canada are needed to understand the ecological effects of PAC mixtures.

Polycyclic aromatic compounds (PACs) in the Canadian environment: Exposure and effects on wildlife.

Polycyclic aromatic compounds (PACs) are ubiquitous in the environment. Wildlife (including fish) are chronically exposed to PACs through air, water, sediment, soil, and/or dietary routes. Exposures are highest near industrial or urban sites, such as aluminum smelters and oil sands mines, or near natural sources such as forest fires. This review assesses the exposure and toxicity of PACs to wildlife, with a focus on the Canadian environment. Most published field studies measured PAC concentrations in tissues of invertebrates, fish, and birds, with fewer studies of amphibians and mammals. In general, PAC concentrations measured in Canadian wildlife tissues were under the benzo[a]pyrene (BaP) guideline for human consumption. Health effects of PAC exposure include embryotoxicity, deformities, cardiotoxicity, DNA damage, changes to DNA methylation, oxidative stress, endocrine disruption, and impaired reproduction. Much of the toxicity of PACs can be attributed to their bioavailability, and the extent to which certain PACs are transformed into more toxic metabolites by cytochrome P450 enzymes. As most mechanistic studies are limited to individual polycyclic aromatic hydrocarbons (PAHs), particularly BaP, research on other PACs and PAC-containing complex mixtures is required to understand the environmental significance of PAC exposure and toxicity. Additional work on responses to PACs in amphibians, reptiles, and semi-aquatic mammals, and development of molecular markers for early detection of biological responses to PACs would provide a stronger biological and ecological justification for regulating PAC emissions to protect Canadian wildlife.

Hepatitis E: a largely underestimated, emerging threat.

Hepatitis E virus has two distinct clinical and epidemiological patterns based on the varying genotypes. Genotypes 3 and 4 cause widespread, sporadic infection in high-income countries and are emerging as the most common type of viral hepatitis in much of Europe. These infections carry significant morbidity and mortality in the growing numbers of immunosuppressed patients or in patients with established liver disease. Furthermore the growing extra-hepatic associations of the virus, including neurological and kidney injury, suggest that it may have been misnamed as a 'hepatitis' virus. This review explores current understanding of the epidemiology, virology and clinical presentations of hepatitis E infection and identifies vulnerable patient groups, who are at serious risk from infection. Guidance is offered regarding the diagnosis, treatment and prevention of this growing public health hazard.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface.

Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.

Continuous phrophylcatic anticonvulsants in selected childrens with febrile convulsions.

The recurrence rate of febrile convulsions is assessed in 108 children who had had either prolonged or repeated initial fits or had both a positive family history and persisting neurological disorder. Only 7 of 40 (17%) who received continuous prophylactic phenobarbitone or primidone for at minimum of 18 months had another fit compared with 40 of 68 (59%) children who were untreated (p less than 0.0005). Indications for continuous therapy are discussed.

A comparative review of the adverse effects of anticonvulsants in children with epilepsy.

Phenobarbital (phenobarbitone) and phenytoin are the most useful anticonvulsants in neonates because adverse effects are most readily reversed when these drugs are used. Most anticonvulsants are very rarely associated with haematological adverse effects. Platelet function is particularly vulnerable to valproic acid (sodium valproate) therapy. Barbiturates and phenytoin can precipitate metabolic bone disease. Although very infrequent, lymphadenopathy is most common with phenytoin, and lupus-like illnesses with ethosuximide. Valproic acid may precipitate underlying metabolic disorders. Nephrolithiasis can occur with topiramate. Liver disease is most likely with felbamate or valproic acid, but can occur with other anticonvulsants. Valproic acid and ethosuximide are the main precipitants of gastrointestinal symptomatology; while valproic acid and vigabatrin are frequently associated with excessive bodyweight gain. Rash is most likely to occur with barbiturates, but there is a high risk of this adverse effect if large doses of lamotrigine are given with valproic acid. Adverse cosmetic effects are most likely with phenytoin, but valproic acid may cause alopecia. All anticonvulsants may cause unwanted neurological effects: when they occur, diplopia is usually precipitated by carbamazepine; tremor by valproic acid; and other motor disturbances are probably most common with phenytoin. Most anticonvulsants can cause drowsiness. Phenobarbital leads anticonvulsants as a cause of behavioural difficulties. Effects of anticonvulsants on cognitive function are difficult to assess, but subtle changes have been reported for all anticonvulsants in use up to the 1980s. Compared with other anticonvulsant drugs, phenytoin and felbamate are more often discontinued as a result of unwanted effects.

Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide.

Based on small numbers of patients, it is possible to make the following suggestions rather than categorical statements. For myoclonic seizures and epilepsies which are not otherwise specified, valproate seems of proven efficacy. Ethosuximide may be a useful adjunct. The exact place of lamotrigine, which controls some myoclonia and makes them worse in other patients, requires further study. The findings are clearer when specific syndromes are considered. Valproate is the treatment of first choice for benign myoclonic epilepsy in infants, myoclonic astatic epilepsy, epilepsy with myoclonic absences, eyelid myoclonia with absences, juvenile myoclonic epilepsy and progressive myoclonus epilepsy. The addition of ethosuximide to valproate can be helpful to those with myoclonic absences, where this combination appears more beneficial than either valproate or ethosuximide alone and in eyelid myoclonia with absences. Lamotrigine can be effective therapy for juvenile myoclonic epilepsy and eyelid myoclonia with absences when used alone and, in conjunction with other antiepileptic drugs (AED) (usually valproate) for early myoclonic encephalopathy, myoclonic-astatic epilepsy and particularly, epilepsy with myoclonic absences. The myoclonia of infantile neuronal ceroid lipofuscinosis respond to lamotrigine. Severe myoclonic epilepsy of infants usually worsens with lamotrigine, but occasionally, children improve. Zonisamide added to clonazepam and valproate or a barbiturate, can reduce the cascade of myoclonia in progressive myoclonus epilepsies for at least 2 years, but relapse may occur thereafter.

Use of ethosuximide and valproate in the treatment of epilepsy.

Ethosuximide is the drug of first choice in absence seizures. Idiosyncratic side effects are rare. Valproate is effective against absence, generalized tonic-colonic, and partial seizures. It is the drug of choice in photosensitive seizures. Valproate is, on the whole, free from unpleasant side effects, but fatal hepatotoxicity and hyperamnionemia have been reported very rarely.

Newer antiepileptic drugs: advantages and disadvantages.

The choice of an antiepileptic drug depends firstly on its efficacy in specific seizure types and epilepsies. However, it is imperative to consider whether possible adverse events will outweigh any benefits. The advantages and disadvantages of vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine and felbamate are considered in some detail, and oxcarbazepine, stiripentol, remacemide, zonisamide and levetiracetam more briefly. Vigabatrin is effective for partial seizures and infantile spasms, but visual field defects are limiting its use. Lamotrigine has a wide spectrum, needs to be prescribed with care. Gabapentin is unlikely to cause adverse effects, but has relatively poor efficacy. Topiramate is widely effective, but can be poorly tolerated. Tiagabine is relatively untried in childhood epilepsies. The use of felbamate is restricted to severe refractory epilepsies. Stiripentol can be effective in severe myoclonic epilepsy in infancy. Zonisamide has a special place in the progressive myoclonus epilepsies. Levetiracetam, remacemide and oxcarbazepine have been used mainly for partial seizures: further studies of their roles in other circumstances are required.

Enteral formula feeds interfere with phenytoin absorption.

Two children treated for status epilepticus had low plasma phenytoin levels during enteral feeding, despite adequate oral dosage. The target range (10-20 mg/l) was achieved when feeds were stopped, or when intravenous phenytoin was used. Enteral feeding may interfere with the absorption of oral phenytoin thereby compromising seizure control.

Practical problems of epilepsy management in children.

The problems associated with the investigation, diagnosis and treatment of epilepsy in children are considered in this paper, together with aspects of intellectual development. In addition, the difficulties encountered in family and school environments are reviewed. The problems which arise when medication is discontinued, and the possible importance of the loss, as well as the acquisition, of a condition, are also discussed.

Management issues in severe childhood epilepsies.

The severe epilepsies of childhood are described briefly and information available on the efficacy of newly developed antiepileptic drugs (AEDs) in their control is reviewed. Therapeutic advances are awaited for early infantile epileptic encephalopathy, early myoclonic encephalopathy, progressive myoclonus epilepsies and Kojewnikow syndrome. West syndrome may respond to vigabatrin, and less predictably to lamotrigine. Lamotrigine can be helpful for severe myoclonic epilepsy and myoclonic absences. Astatic seizures may be dramatically controlled by lamotrigine, whereas vigabatrin may worsen myoclonic attacks. In the Lennox-Gastaut syndrome, the efficacy of felbamate has been demonstrated by a controlled trial; vigabatrin and lamotrigine can also be helpful. Non-idiopathic partial and secondary generalized epilepsies are responsive to vigabatrin in a useful percentage of cases, and some children improve with felbamate, lamotrigine or striripentol. A trial which compares the efficacies of the newer AEDs against each other could provide very useful information for the clinician.